Recent research indicates that ovaries may have a significant impact on postmenopausal health, contradicting the belief that they become completely inactive after menopause. Studies show that immune cells infiltrate the ovaries of aging mice, linking these organs to chronic postmenopausal inflammation.
“We assumed the ovaries fulfilled their purpose after reproduction,” stated Francesca Duncan from Northwestern University. “Our findings were quite unexpected.”
In March, Duncan and her team published a study that explored the protein profiles of postmenopausal women aged 50 to 75. Contrary to their expectations of uniformity, they discovered that the molecular signatures of the ovaries evolve dramatically over time, challenging the notion of their inactivity.
To delve deeper, Duncan’s team is analyzing mouse ovaries, focusing on tissue and gene expression at different life stages: young (2 months), reproductive (18 months), and post-reproductive (24 months). Despite lacking menstrual cycles, aging mice experience a decline in egg reserves leading to irregular cycles, similar to human menopause. “We recognize that the hormonal changes mirror what happens in humans as they age,” Duncan noted.
Initial findings confirmed some expectations; older ovaries exhibited a loss of egg-producing follicles and increased scarring. However, the study also found heightened gene activity associated with inflammation and immune response as aging progressed. The number of immune cells, including T cells and macrophages, rose in tandem with age.
Further investigation is crucial to clarify the implications of these changes for immunity and overall health. Duncan suggests this transformation in the ovaries might indicate a loss of reproductive function coupled with an increase in immune activity, which may not be beneficial. “As ovaries transition, there could be an uptick in inflammatory signaling that interacts with other bodily systems,” she explained.
While the current study focuses on mice, Diana Laird and her team at UCSF propose that similar immune modifications may be occurring in human ovaries, based on shared reproductive traits across species. “Both our species cease cyclical activity once the ovarian supply is depleted. Other phenomena, like fibrosis and altered nerve supply, are also present,” she asserted.
Although the rationale behind this evolutionary change in older mice remains unclear, it may have historically provided a survival advantage by enabling immune cell reservoirs at a time when fewer individuals lived to old age. Today, however, it poses risks of inflammation and autoimmune disorders.
This research prompts a reevaluation of the ovaries’ importance post-menopause. Although typically seen as dormant, they continue to release hormones like androgens, crucial for maintaining bone density and libido. Laird emphasized the need for more in-depth studies, linking immune changes in the ovaries to increased inflammation and conditions like rheumatoid arthritis after menopause. “This emphasizes the necessity for detailed investigations into the post-reproductive ovary’s cellular and molecular components,” she concluded.
From cognitive fog to heightened anxiety, the mental health effects of menopause are well-documented. However, recent findings indicate that the neurological changes are more severe than previously understood, possibly explaining the increased risk of Alzheimer’s disease in women.
Roberta Brinton from The University of Arizona explains that these brain changes can be compared to renovating a house: “It becomes a different brain.”
These findings underscore the impact of midlife on brain health and the astonishing resilience of this organ.
“Menopause often reveals neurological vulnerabilities,” Brinton states. “This phase is critical for identifying and addressing neurological risks in women.”
Menopause, which typically occurs around age 50, marks the end of menstruation and is associated with diminished production of reproductive hormones such as estrogen and progesterone. This leads to a spectrum of symptoms, including sleep disturbances, hot flashes, and mood swings.
Symptoms can start in the perimenopausal phase, characterized by significant estrogen fluctuations, which greatly affect brain function, especially since estrogen is essential for various brain activities. This hormone contributes to energy production in the brain by facilitating glucose conversion, making up about 25% of its energy supply. A sudden drop in estrogen can initiate a “bioenergetic crisis,” as Brinton describes.
Evidence of this energy crisis is apparent in MRI studies. In 2021, Brinton and colleagues analyzed the brain activity of 161 women, identifying three distinct groups: premenopausal, perimenopausal, and postmenopausal.
On average, postmenopausal women exhibited about 20% lower glucose metabolism in memory-related brain regions compared to their premenopausal counterparts. Perimenopausal women showed a 10% decrease.
Animal studies suggest that the brain adapts to energy deficits by shifting to alternative fuel sources, primarily lipids. Brinton notes that during menopause, the brain utilizes lipids for energy from the white matter.
White matter acts as a communication network in the brain, facilitating message transmission. In Brinton’s research, a notable 10% reduction in white matter was observed post-menopause compared to pre-menopause, emphasizing the menopausal brain’s dependence on lipids.
Related findings imply potential links between menopause and Alzheimer’s disease, suggesting that hormonal changes might set the stage for cognitive decline. This may help explain why women represent two-thirds of Alzheimer’s cases, and those who enter menopause early face a higher risk.
Despite the assertions about the menopausal brain’s fuel needs, skepticism exists among researchers. In a groundbreaking long-term study, Pauline Maki scanned the brains of 242 women aged 40 to 60. Preliminary findings indicated no significant differences in brain volume, including white matter, across different menopausal stages.
This discrepancy may result from variations in study demographics, leading to the ongoing need for deeper investigation. As more studies are released, the understanding of these findings may evolve.
Regardless, evidence indicates that the loss of estrogen can impair verbal memory, particularly during perimenopause. Maki emphasizes, “These cognitive abilities are highly sensitive to declining estrogen levels.”
However, it’s important to note that most women in perimenopause score within normal ranges on verbal memory tests. “It’s not indicative of dementia,” Maki clarifies, “but there are still noticeable changes.”
Impact of Decreased Estrogen on Memory in Perimenopause
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In a recent study, Maki and her team assessed the brain activity of nearly 200 postmenopausal women performing memory tasks. The results indicated that higher estrogen levels correlated with improved memory performance and enhanced activation of brain areas linked to memory.
Another unpublished study from Maki’s team has connected lower postmenopausal estrogen levels to diminished connections between the hippocampus and prefrontal cortex, which are essential for memory function.
These findings illuminate how hormone replacement therapy (HRT), which restores estrogen levels, can enhance cognitive performance in perimenopausal women. Research indicates a connection between HRT and a reduced likelihood of Alzheimer’s disease. However, timing plays a crucial role; most studies suggest that the protective effects of HRT are strongest for those who initiate treatment up to 10 years before menopause.
Early estrogen introduction may help the brain maintain its energy supply to white matter, according to Brinton; once this adjustment occurs, it may be too late for intervention.
Additionally, HRT alleviates hot flashes, which can severely disrupt sleep. “Chronic sleep deprivation is detrimental to brain health,” notes Maki.
Maki’s research has also indicated that local anesthetics can interrupt neural systems responsible for temperature regulation in the spinal cord, potentially aiding in memory improvement for menopausal women. Brinton’s team is also exploring non-hormonal agents that target estrogen receptors to minimize hot flashes and possibly lower Alzheimer’s risk, currently undergoing Phase II trials.
Encouragingly, the brain seems capable of adaptation even without HRT, with studies showing shifts in brain structures after menopause. A recent investigation involving around 11,000 women discovered that gray matter volume decreases during perimenopause, but some areas may rebound after menopause.
The research indicates no significant disparity in memory performance between premenopausal and postmenopausal women. However, those in the latter group appeared to recruit more pronounced activation in the dorsolateral prefrontal cortex, crucial for memory tasks. This suggests that the brain may adapt to hormonal changes by integrating additional neural circuits to compensate.
While the transition may elevate Alzheimer’s risk for some, Maki emphasizes the importance of managing other potential risk factors like high blood pressure and hearing loss.
Despite the rapid cognitive alterations associated with menopause, enduring cognitive issues are not universally anticipated. “All women undergo menopause,” Maki asserts. “However, not all will develop dementia or persistent brain fog. The brain’s transition during menopause highlights its remarkable capacity for reorganization and adaptation in response to change.”
Therapy that balances testosterone and estrogen reduces menopausal symptoms
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The menopause can bring a host of challenging symptoms such as mood fluctuations, difficulties in concentration, and a decline in sexual drive. Hormone replacement therapy is commonly sought to alleviate these issues, primarily focusing on restoring estrogen and progesterone levels, which drop significantly during midlife. Recent studies indicate that testosterone may also play a crucial role in managing various menopausal symptoms beyond just libido, including mood improvement and muscle retention.
While typically categorized as a male hormone, testosterone is also present in women, albeit at lower levels—approximately ten times less than in men. Dr. Sarah Glynn, a contributor to menopause treatment guidelines at the British Society of Sexual Medicine, notes that limited understanding of testosterone’s effects has hindered research in this area, but recent findings are changing that narrative. Increasing evidence highlights the hormone’s crucial role in women’s sexual health and its potential benefits for cognitive, muscular, skeletal, and urinary function.
Approximately half of a woman’s testosterone is produced by the ovaries, with the remainder being synthesized by the adrenal glands. Testosterone levels generally peak in the 20s and begin to decline gradually after age 30, with production halving by middle age. Dr. Sharon Parrish from Cornell University mentions that although this decline often coincides with menopause, it may not be a direct result of it.
We know little about the health implications of this decline, but it is evident that it can reduce sexual interest. “[Testosterone] plays a critical role in sexual function,” states Dr. Joan Pinkerton from UVA Health in Virginia, influencing factors such as sexual arousal, desire, and lubrication. Consequently, it makes sense that nearly half of menopausal and postmenopausal women experience issues with sexual desire, with a leading cause being hypoactive sexual desire disorder (HSDD)—a distressing lack of sexual fantasies or desire lasting at least six months. In a survey of 1,800 postmenopausal women in Europe, over one-third reported reduced desire and more than half indicated decreased interest in sex.
The notion that low testosterone contributes to diminished sex drive was established in the 1940s. Numerous studies have consistently shown that testosterone replacement therapy can enhance sexual function in menopausal women. For instance, a 2005 report involving 533 women who underwent hysterectomies noted that those receiving testosterone patches along with estrogen reported more satisfying sexual experiences than those on estrogen alone. A similar study in 2010 corroborated these findings with 272 menopausal participants.
In 2019, a meta-analysis encompassing over 80 studies involving 8,480 women demonstrated that testosterone treatment for postmenopausal women significantly heightened sexual desire and increased frequency of sexual satisfaction, arousal, orgasm, and overall self-esteem. This study garnered support from approximately 12 medical organizations, including the International Menopause Society, the Royal College of Obstetricians and Gynecologists, and the North American Menopause Society, which endorsed the use of testosterone for HSDD.
Testosterone enhances sex drive by interacting with brain receptors that activate the neural pathways governing desire, explains Parrish. Thus far, only four countries—Australia, New Zealand, South Africa, and the UK—have approved women-specific testosterone products. The U.S. Food and Drug Administration (FDA) has yet to approve these, citing insufficient data on potential long-term side effects. Nevertheless, Professor Parrish argues this caution is unwarranted, stating that some studies have tracked participants for years without revealing increased risks of cardiovascular, breast, or uterine issues.
“Most healthcare providers focused on menopausal women seek an FDA-approved testosterone therapy that is both safe and effective. We genuinely believe there’s an urgent need for such treatments, particularly concerning sexual health,” Pinkerton comments.
Finding the Right Balance
Women report feeling more like themselves after menopausal hormone treatment
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Some medical professionals believe that testosterone therapy can extend benefits beyond just sexual health. A 2023 analysis covering seven studies found that testosterone may contribute to increased muscle mass, reduction in body fat, and improvements in insulin sensitivity and cholesterol levels. In 2024, Glynne and her team assessed hormone therapy in 510 women experiencing perimenopause and menopause who were also on estrogen. After four months, around 50% reported fewer anxiety episodes and less crying, while approximately 40% noted improvements in mood, focus, and fatigue. More than a third experienced enhanced memory and reduced irritability. “Common feedback is that women feel more like themselves—stronger and more empowered,” states Glynn.
Yet, skepticism remains. Pinkerton cautions that many of these studies lacked control groups, relying heavily on self-reports, which raises questions about whether improvements were genuinely due to testosterone or might be attributed to a placebo effect. “There’s some evidence concerning cognition, mood, muscle strength, cardiovascular health, and bone health, but the lack of substantial randomized controlled trial efficacy and safety data doesn’t justify recommendations for these issues,” Parrish remarks.
Most clinical trials combine testosterone therapy with estrogen, though some studies indicate that testosterone alone can effectively enhance sexual function. However, due to frequent side effects such as acne and excessive hair growth, it is generally not advised. Glynne prefers to prescribe estrogen initially, adding testosterone only if symptoms remain unresolved.
Experts agree that comprehensive clinical trials focusing on testosterone’s impacts beyond sexual health are urgently needed. Questions concerning optimal timing, dosage, and duration also persist, as Pinkerton highlights.
What stands out is that many current menopause treatments fall short for numerous individuals, particularly those with a history of hormone-sensitive breast cancer who are hesitant to undergo estrogen therapy due to concerns regarding potential tumor growth or recurrence. “This represents a significant gap in knowledge, and we need more data,” Glynn concludes.
A decrease in estrogen during menopause may affect cognitive function
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Commencing hormone replacement therapy (HRT) within five years of the onset of postmenopause appears to decrease the likelihood of developing Alzheimer’s disease. In contrast, starting HRT later in life may have adverse effects, indicating that the timing of the therapy is crucial for its impact on the brain.
Women face a greater risk of developing Alzheimer’s, particularly after menopause, compared to men. This heightened risk may be linked to reduced estrogen levels, which play vital roles in brain energy regulation and inflammation. Consequently, HRT has surfaced as a potential method to reduce Alzheimer’s risk following menopause. However, research on its effectiveness has produced mixed outcomes.
To investigate this, Fnu Vaibhav Pandit Bagwat Deira Sharma from Health Science University in India and his team analyzed 53 studies encompassing over 8.4 million postmenopausal participants regarding Alzheimer’s disease prevalence.
In a randomized controlled trial, participants receiving HRT exhibited, on average, a 38% greater risk of developing Alzheimer’s compared to those not on HRT. Conversely, observational studies suggested a 22% reduction in Alzheimer’s risk among HRT users.
Vaibhav presented these findings at a meeting with the American Nerve Association in Maryland on September 15th, noting that the disparity is likely age-related. Most subjects in the randomized trial were over 65, while those in observational studies tended to be younger. Further analysis revealed that individuals who initiated HRT within five years post-menopause had a decreased risk of Alzheimer’s by 32% over a follow-up period ranging from five years to others that consumed their lifetime.
“This transition during menopause represents a neurological shift,” stated Roberta Brinton from the University of Arizona, who was not part of the research. As estrogen levels decline, the brain seeks alternative energy sources. There is some evidence suggesting that this reallocation may utilize compounds meant for brain function while sacrificing others, leading to potential neurodegeneration. She posits that HRT may either initiate or halt this transition during menopause. However, if the brain has already undergone this shift, HRT may be ineffective.
“More research is essential to clarify this perplexity,” remarked Vaibhav. Without a clearer comprehension of HRT’s impact, he warns that “women may miss out on advantages, and some may inadvertently face harm.”
New research has identified four genes that, if altered, could impact the age at which menopause occurs. These genes (ETAA1, ZNF518A, PNPLA8, and PALB2) were found to cause women to experience menopause two to 5.5 years earlier if they have only one functioning copy. The study, conducted by scientists from the Universities of Exeter, Cambridge, and Wellcome, was published in Nature.
Understanding these genetic changes is crucial for potential therapies to extend reproductive lifespan and plan for the impact of menopause on women’s career and life plans. The study also found links between these genetic changes and cancer risk, highlighting the importance of further research in this area.
These genetic changes can lead to the DNA damage of eggs, affecting the age at which menopause occurs. The study analyzed data from 106,973 postmenopausal women and found that rare genetic changes have a significant impact on the age at menopause. These changes not only shed light on menopause but also provide insight into disease risks.
Dr. Stasha Stankovic, Dr. Hilary Martin, and Professor John Perry, members of the research team, emphasized the importance of understanding ovarian function for reproductive health and disease prevention. They hope that further research in this area will lead to new treatments for ovarian-centered diseases and help predict age at menopause more accurately.
The study also revealed that changes in a mother’s DNA can impact the DNA passed on to her child, showing a link between genetic mutations and the rate of DNA changes. This discovery is significant in understanding the biological mechanisms behind infertility, reproductive disorders, and disease predisposition.
About our experts
Dr. Stasha Stankovic is a reproductive geneticist with a PhD in Reproductive Genomics from the University of Cambridge. Her research has been published in top scientific journals such as Nature, Nature Medicine, Nature Genetics, and Cell Genomics.
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